Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1-c1ccccc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1O

Procedure:
In step (1) of Reaction Scheme 1, a 2-hydroxybiphenyl of Formula II is nitrated using nitric acid in the presence of acetic acid to provide a 2-hydroxy-3-nitrobiphenyl of Formula III. A preferred method of carrying out this reaction is as follows. The biphenyl of Formula II is dissolved in glacial acetic acid at a temperature of 15° to 20° C. Concentrated nitric acid is then added thereto and the resulting mixture is stirred for a short period of time (usually less than about one hour). Thereafter the mixture is diluted with an equal volume of water. The 2-hydroxy-3-nitrobiphenyl of Formula III is separated from the mixture, usually as an oil, and is triturated with hot hexane and purified by chromatography. As an alternative to conducting step (1), known 2-hydroxy-3-nitrobiphenyls may be employed directly in step (2) below.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.[H-].[Na+].[H][H].S(OC)(O[CH3:21])(=O)=O>CN(C=O)C.CCCCCC>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:21])=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Nc1ccc2ccc(O)cc2c1
Reactant: COS(=O)(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc2ccc(N)cc2c1

Procedure:
2-Amino-7-hydroxynaphthalene (18.6 g, 0.117 mol) was added in portions to hexane-rinsed NaH (60%, 5.1 g, 0.127 mol) in dry DMF (dimethylformamide; 100 ml) at 0° C. The solution was stirred under argon for 10 minutes until hydrogen evolution had ceased, whereupon dimethyl sulfate (11 ml, 0.116 mol) was added dropwise via syringe at 0° C. until O-methylation was complete by TLC monitoring. The reaction was carefully quenched with 6N HCl to pH 1, and partitioned between ether and water, thus separating the naphthylamine hydrochloride from organic impurities. After washing the ether layer with 6N HCl, the aqueous layers were combined, neutralized with NaOH pellets to pH 8 and partitioned with EtOAc to recover the free amine in the organic layer. The basic aqueous layer was washed twice with EtOAc, and the combined EtOAc layers were dried over Na2SO4 and evaporated. Upon removal of DMF under high vacuum, the product mixture crystallized. Crystals of 2-amino-7-methoxynaphthalene (19.4 g, 96.5%) were collected from MeOH, m.p. 157° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][C@H:4]([O:9][C@H:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:30][O:31][CH2:32][CH2:33][Br:34]>C(#N)C>[Br-:34].[CH3:8][O:7][C:5]([C@@H:4]([O:9][C@H:10]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N+:19]([CH2:33][CH2:32][O:31][CH3:30])[CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)[CH2:3][CH:2]([CH3:29])[CH3:1])=[O:6]
Reactant: COCCBr
Reactant: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1
Solvent: CC#N
Product: COCC[n+]1cccc(-c2ccc([C@H](O[C@@H](CC(C)C)C(=O)OC)c3ccccc3)cc2)c1
Product: [Br-]
Reaction time: 18 h

Procedure:
A solution of methyl (2S)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanoate from example 36 step 2 (740 mg, 1.9 mmol) and 2-bromoethyl methyl ether (1.32 g, 9.5 mmol) in acetonitrile (10 mL) was heated in a pressure tube emersed in an oil bath at 120+ C. for 18 hours. The mixture was concentrated and the residue slurried with diethyl ether (25 mL) 2 times followed by decanting and then pumped on by high vacuum to obtain the title compound as a foam.
Reaction SMILES: C1O[C:4]2([CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=3)[CH2:5]2)OC1.C([Li])(C)(C)C.[C:21](=[O:23])=[O:22].C1C[O:27]CC1>>[C:5]1(=[O:27])[C:6]2[C:11](=[CH:10][C:9]([C:21]([OH:23])=[O:22])=[CH:8][CH:7]=2)[CH2:12][CH2:13][CH2:4]1
Reactant: O=C=O
Reactant: C1CCOC1
Reactant: Brc1ccc2c(c1)CCC1(C2)OCCO1
Agent: [Li]C(C)(C)C
Product: O=C(O)c1ccc2c(c1)CCCC2=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6-Bromo-2-tetralone ethylene ketal (2.2 g, 8.15 mmol) was dissolved in anhydrous THF (30 mL), cooled to -78° C. and treated with tert-butyllithium (12.05 mL, 20.4 mmol, 1.7M in pentane) under an atmosphere of nitrogen. After stirring for 30 minutes, anhydrous carbon dioxide gas was passed through the reaction mixture for 20 minutes at -78° C. The suspension was then allowed to warm to ambient temperature. The solution was quenched with water and acidified with 1N HCl, then extracted 2×EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated in vacuo to a pale brown oil. The oily residue was applied to a silica flash chromatography column and eluted with 30%-50% EtOAC in hexanes to yield tetralone-6-carboxylic acid, ethylene ketal 1.06 g (55%) of a slowly crystallizing solid. NMR. MS.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].S(Cl)(Cl)=O.[C:18]1([CH3:30])[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH2:28]O)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl>[Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH2:28][CH2:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([CH3:30])=[CH:19][CH:20]=1)(=[O:26])=[O:25])=[O:9])(=[O:4])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)CCO)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)CCOC(=O)c2cccc(S(=O)(=O)Cl)c2)cc1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A mixture of 3-(chlorosulfonyl) benzoic acid (Intermediate 73, 5.51 g, 0.025 mol) and thionyl chloride (17.85 g, 11 mL, 0.15 mol) was refluxed for 1 hr. Excess thionyl chloride was distilled off at atmospheric pressure and finally at reduced pressure to give crude acid chloride. To a mixture of the crude acid chloride and 2-(p-tolylsulfonyl)ethanol (4.8 g, 0.024 mol) in dichloromethane (50 mL) was added triethylamine (2.52 g, 0.025 mol) at room temperature. TLC showed the reaction mixture was complete after 1 hr. The reaction mixture was washed with water (2×25 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give 10 g of a viscous oil. The oil was purified by flash chromatography (silica gel, 25 to 50% ethyl acetate in hexane) to give 6.1 g (63%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:25][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:25])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Solvent: C1CCOC1
Product: CC(O)(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(5,7-difluoro-quinolin-6-yl)-methanone (Stage 182.3, 3.05 g, 8.41 mmol) was suspended in THF (65 mL) and the mixture was cooled down to 0° C. with an ice bath. Then the methylmagnesium bromide (1.4 M, 15.01 mL) was added slowly. The RM was stirred for 30 min and was then allowed to warm up to rt. After 2 h, it was quenched with a few mL of water. The solution was filtered. The solid residue was washed with water and the filtrate extracted with EtOAc twice. Then the organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The crude was purified with DCM and MeOH by MPLC to give the title compound as a yellow solid (tR 0.9 min (conditions 2), MH+=361).
Reaction SMILES: Cl.[CH:2]12[O:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][NH:4][CH2:3]2.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CC(C)=O>[CH:6]12[O:9][CH:2]([CH2:8][CH2:7]1)[CH2:3][N:4]([C:15]1[N:16]=[C:11]([Cl:10])[N:12]=[C:13]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]3)[N:14]=1)[CH2:5]2
Reactant: C1CC2CNCC1O2
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(Cl)n2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)CC1
Temperature: 72.5 °C
Reaction time: 2 h

Procedure:
To a solution of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.49 g, 3.3 mmol) in water (18 mL) was added a suspension of tert-butyl 4-(4,6-dichloro-1,3,5-triazin-2-yl)piperazine-1-carboxylate (1.0 g, 3.0 mmol) in acetone (about 10 mL). The suspension was stirred magnetically while solid sodium carbonate (0.70 g, 6.6 mmol) was added in a single portion. The mixture was stirred for two hours while heating in a 70-75° C. in an oil bath. After allowing the mixture to cool to room temperature, the title compound was removed by filtration, washed with water, and dried under vacuum.
Reaction SMILES: [F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C1COCC1.O>[F:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: Fc1cccc(OCCCCOC2CCCCO2)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: OCCCCOc1cccc(F)c1F
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(2,3-difluorophenoxy)-butoxy]-tetrahydropyran (20) (1 equi.) and commercially available para-toluenesulfonic acid (21) (0.1 equi.) in methanol:THF (1:1) (3 mL/mmole), water (0.005 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (10% EtOAc/hexanes) gave 4-(2,3-difluorophenoxy)-butan 1-ol (22), as a white solid (84%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH:16]1(O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCc1ccc(O)c(Br)c1
Reactant: OC1CCCCC1
Product: CCOC(=O)CCc1ccc(OC2CCCCC2)c(Br)c1

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 in Reference Example 2 (Step e-2), ethyl 3-(3-bromo-4-hydroxyphenyl)propionate and cyclohexanol were reacted and treated to obtain ethyl 3-(3-bromo-4-cyclohexyloxyphenyl)propionate (355 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 17 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate 8:1), the above product was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (330 mg), 2 M aqueous sodium carbonate (0.9 ml) and (Ph3P)4Pd (105 mg) and treated to obtain the title compound (Intermediate 68, 260 mg).
Reaction SMILES: C[N:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[Li][CH2:8]CCC.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.O>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][CH2:8][C:3]1[CH2:4][CH2:5][CH2:6][N:2]=1
Reactant: CN1C=CCC1
Reactant: [Li]CCCC
Reactant: Clc1ccccc1CBr
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccccc1CCC1=NCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.1 3 ml of 1-methylpyrroline are dissolved in 25 nil of THF and deprotonated at −78° C. for 30 minutes using 22.6 ml of BuLi (1 M in hexane). 6.5 g of 2-chlorobenzyl bromide are dissolved in 25 ml of THF and added dropwise at the temperature indicated. After 30 minutes, the mixture is allowed to warm to RT for 12 hours. For work-up, 50 ml of water are added, and the mixture is extracted to exhaustion with dichloromethane. The combined organic phases are dried over sodium sulfate, evaporated and purified by chromatography on silica gel, giving 4.5 g of 5-[2-(2-chlorophenyl)ethyl]-3,4-dihydro-2H-pyrrole as a colourless oil, which is employed in the next reaction; Rt.: 1.303 min; [M+H]+208.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16]
Reactant: OC1CCCCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of cycloheptanol (0.600 mL, 5.0 mmol) in dichloromethane (15 mL) is added rhodium (II) acetate dimer (21 mg) followed by ethyl diazoacetate (0.60 g, 5.7 mmol). The reaction mixture is stirred at RT for 10 min. The reaction mixture is rotary evaporated, and the residue dissolved in Et2O, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 0.960 g of the product 411. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.06 (s, 2H), 3.50 (m, 1H), 1.93 (m, 2H), 1.7-1.4 (m, 8H), 1.4-1.3 (m, 2H), 1.28 (t, 3H); MS: m/z 201 (M++1).
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[C:29]1([CH3:39])[C:30](S(O)(=O)=O)=[CH:31][CH:32]=[CH:33][CH:34]=1.[CH2:40]([OH:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11]([O:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([O:23][CH2:39][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: OCc1ccccc1
Reactant: CCCCC[C@@H](CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC)OC(C)=O
Product: CCCCC[C@@H](CC[C@H]1CCC(OCc2ccccc2)(OCc2ccccc2)[C@@H]1CCCCCCC(=O)OC)OC(C)=O

Procedure:
A solution of 2 g. of 1 methyl 15(S)-acetoxy-9-oxo prostanoate (Example 52) and 25 mg. of p toluene sulfonic acid in 65 ml. of benzylalcohol is stirred at 100°C. for 6 hours. The solution is concentrated to near dryness under reduced pressure. The residue is diluted with ether and the resulting solution is washed with 5% sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to afford 2.5 g. of product.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][C:23](=O)OCC4C=CC=CC=4)=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.Br.[C:36](O)(=O)C>>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:21]([NH:22][CH2:23][CH3:36])=[CH:20][CH:19]=[CH:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Nc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CCNc1cccn2c(=O)c(O)c(C(=O)NCc3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)carbamate in acetic acid was added HBr (30% in AcOH). The solution was stirred at room temperature for 2 hours and afterwards the solvent was removed under reduced pressure. The residue was dissolved several times in toluene and the solvent removed under reduced pressure. The resulting solid was dissolved in 1,2-dichloroethane-MeOH (1:1), acetaldehyde and sodium cyanoborohydride were added, and the mixture stirred at room temperature. After 30 minutes the solvent was removed under reduced pressure and the residue washed with H2O.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([N+:25]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:10]([NH2:25])[CH:9]=2)=[N:6][NH:5][C:4](=[O:28])[CH2:3]1
Reactant: [H][H]
Reactant: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc(C3=NNC(=O)CC3C)cc2N)cc1

Procedure:
9.8 gm of 5-methyl-6-[3-nitro-4-(4-methoxy-benzoylamino)-phenyl]-3-oxo-4,5-dihydro-2H-pyridazine were dissolved in 1000 ml of ethanol and hydrogenated for 24 hours at room temperature with a hydrogen pressure of 5 bar in the presence of 1 gm of 10% palladium charcoal. The obtained precipitate was suction filtered and used in the next step without removing the catalyst. A further fraction of the product can be obtained from the mother liquors.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Li]CCCC.[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:17])[CH3:16].CN([CH:34]=[O:35])C>C1COCC1>[C:15]([O:19][C:20](=[O:30])[NH:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH:34]=[O:35])=[C:24]([Cl:29])[N:23]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Cl)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C=O)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylethylamine (7.4 mL, 53.2 mmol) in THF was added n-BuLi (18.8 mL, 47.1 mmol, 2.5 M solution in hexanes) at −78° C., and allowed to stir at 0° C. of 30 minutes. The reaction mixture was again cooled to −78° C. and a solution compound tert-butyl(4,6-dichloropyridin-2-yl)carbamate (4.0 g, 15.2 mmol) in THF (20.0 mL) was added dropwise and stirred for 1 h at the same temperature. After 1 h, DMF (8.08 g, 36.7 mmol) was added at the same temperature and stirred for 30 minutes. After confirming the completion of starting material by TLC, the reaction mixture was quenched with saturated ammonium chloride solution extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to get crude product which was purified by column chromatography (hexanes:ethyl acetate=4:1) to afford product. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 10.95 (s, 1H), 10.22 (s, 1H), 7.95 (s, 1H), 1.47 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30]([OH:35])[CH:31]=[C:32]([F:34])[CH:33]=1>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:35][C:30]2[CH:31]=[C:32]([F:34])[CH:33]=[C:28]([Cl:27])[CH:29]=2)=[N:3][CH:4]=1
Reactant: Oc1cc(F)cc(Cl)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1cc(F)cc(Cl)c1)c1ccc(C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and 3-chloro-5-fluorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.6 Hz), 8.17 (1H, d, J=2.6 Hz), 7.97 (2H, d, J=8.4 Hz), 7.88–7.80 (1H, m), 7.40 (2H, d, J=8.4 Hz), 7.10–7.02 (1H, m), 7.00–6.94 (1H, m), 6.87–6.80 (1H, m), 5.43–5.27 (1H, m), 1.68–1.55 (12H, m); MS (ESI) m/z 505 (M+H)+, 503 (M−H)−.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]([CH:16]3[CH2:18][CH2:17]3)[C:8]2=[O:19])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:30]1[N:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1>CS(C)=O.CCOC(C)=O>[CH:16]1([N:9]2[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:7]([C@H:5]3[CH2:6][C@H:3]([NH:2][C:30]4[N:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH2:4]3)[C:8]2=[O:19])[CH2:17][CH2:18]1
Reactant: Clc1ncc2ccccc2n1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3cccnc32)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CC2)c2cccnc2n1[C@H]1C[C@H](Nc2ncc3ccccc3n2)C1
Temperature: 120 °C

Procedure:
A mixture of 3-(trans-3-aminocyclobutyl)-1-cyclopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.458 g, 1.63 mmol), Hunig's base (Aldrich, 1.139 ml, 6.52 mmol), and 2-chloroquinazoline (Waterstone, 0.322 g, 1.956 mmol) in DMSO (3.26 ml) was heated to 120° C. overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. Purification by Biotage (0-100% EtOAc/hexane, 25 g Biotage column) produced 1-cyclopropyl-3-(trans-3-(quinazolin-2-ylamino)cyclobutyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.244 g, 0.601 mmol, 37% yield). M+1: 373.0. 1H NMR (300 MHz, MeOH) δ ppm 0.93-1.03 (m, 3 H) 1.06-1.19 (m, 3 H) 2.47-2.64 (m, 2 H) 2.85-3.00 (m, 2 H) 3.42-3.60 (m, 2 H) 5.25-5.45 (m, 1 H) 7.04-7.20 (m, 1 H) 7.20-7.35 (m, 1 H) 7.48-7.64 (m, 3 H) 7.64-7.83 (m, 3 H) 7.99-8.14 (m, 1 H) 8.99-9.12 (m, 1 H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[OH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:3]([NH:2][S:27]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=1)(=[O:29])=[O:28])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: NC(CC(=O)O)c1ccccc1O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
1.1 g of 3-amino-3-(2-hydroxyphenyl)propionic acid hydrochloride, prepared according to J. Agric. Food Chem., 1977, 25, 965, are dissolved in 25 ml of dioxane and 10 ml of 1N NaOH are added; 1.12 g of 2-naphthalenesulphonyl chloride are gradually added while maintaining the pH at 11.5-12 by addition of 1N NaOH. After stirring for 2 hours at RT, the reaction medium is diluted in water, washed with EtOAc (twice) and then acidified to pH=1.5-2 by addition of 6N HCl. The white precipitate formed is drained, washed with water and dried in order to obtain 0.82 g of the expected product, m.p.=190-200° C.